9-deoxy-9-methylene-16-phenyl-5,6-didehydro-pgf2 or 4,4,5,5-tetradehydro-pgf1 compounds

ABSTRACT

The present invention relates to novel 9-deoxy-9-methylene-16-phenyl-5,6-didehydro-PGF 2 , or 4,4,5,5-tetradehydro-PGF 1  compounds. These compounds are useful pharmacological agents, and are useful for the same purposes as the corresponding PGE-type compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 786,249, filed Apr. 11, 1977, now issued as U.S. Pat. No. 4,118,584.

The present invention relates to novel 9-deoxy-9-methylene-16-phenyl-5,6-didehydro-PGF₂, or 4,4,5,5-tetradehydro-PGF₁ compounds, the essential material constituting a disclosure of which is incorporated here by reference from U.S. Pat. No. 4,118,584. 

I claim:
 1. A prostaglandin analog of the formula ##STR1## WHEREIN Y₂ is trans-CH═CH-- or --CH₂ CH₂ --; wherein M₁ is ##STR2## wherein R₅ is hydrogen or methyl; WHEREIN L₁ is ##STR3## or a mixture of ##STR4## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro;Wherein Z₉ is --C.tbd.C--CH₂ --(CH₂)_(g) --CH₂ -- or --CH₂ --C.tbd.C--(CH₂)_(g) --CH₂ -- wherein g is one, 2, or 3;Wherein T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, and s is zero, one, 2, or 3, the various T's being the same or different, with the proviso that not more than two T's are other than alkyl; Wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms, inclusive, or a pharmacologically acceptable cation, and the 1,11- or 1,15-lactones thereof.
 2. A prostaglandin analog according to claim 1, wherein Y₂ is --CH₂ CH₂ --.
 3. A prostaglandin analog according to claim 2, wherein Z₉ is --CH₂ --C.tbd.C--(CH₂)_(g) --CH₂ --.
 4. A prostaglandin analog according to claim 3, wherein M₁ is ##STR5##
 5. 9-Deoxy-9-methylene-15-epi-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-13,14-didehydro-PGF₁, a prostaglandin analog according to claim
 4. 6. A prostaglandin analog according to claim 3, wherein M₁ is ##STR6##
 7. A prostaglandin analog according to claim 6, wherein s is zero, or one and T is chloro, fluoro, or trifluoromethyl.
 8. A prostaglandin analog according to claim 7, wherein g is
 3. 9. 9-Deoxy-9-methylene-2a,2b-dihomo-15-methyl-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-PGF₁, a prostaglandin analog according to claim
 8. 10. 9-Deoxy-9-methylene-2a,2b-dihomo-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-PGF₁, a prostaglandin analog according to claim
 8. 11. A prostaglandin analog according to claim 7, wherein g is
 1. 12. A prostaglandin analog according to claim 11, wherein at least one of R₃ and R₄ is methyl.
 13. A prostaglandin analog according to claim 12, wherein R₃ and R₄ are both methyl.
 14. 9-Deoxy-9-methylene-16-methyl-4,4,5,5-tetradehydro-16-phenyl-18,19,20-trinor-13,14-dihydro-PGF.sub.1, a prostaglandin analog according to claim
 13. 15. A prostaglandin analog according to claim 11, wherein at least one of R₃ and R₄ is fluoro.
 16. A prostaglandin analog according to claim 15, wherein R₃ and R₄ are both fluoro.
 17. 9-Deoxy-9-methylene-16,16-difluoro-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-PGF₁, a prostaglandin analog according to claim
 16. 18. A prostaglandin analog according to claim 11, wherein R₃ and R₄ are both hydrogen.
 19. A prostaglandin analog according to claim 18, wherein R₅ is methyl.
 20. 9-Deoxy-9-methylene-15-methyl-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-PGF₁, a prostaglandin analog according to claim
 19. 21. A prostaglandin analog according to claim 18, wherein R₅ is hydrogen.
 22. 9-Deoxy-9-methylene-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-PGF₁, a prostaglandin analog according to claim
 21. 23. A prostaglandin analog according to claim 2, wherein Z₉ is --C.tbd.C--CH₂ --(CH₂)_(g) --CH₂ --.
 24. A prostaglandin analog according to claim 2, wherein M₁ is ##STR7##
 25. A prostaglandin analog according to claim 24, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 26. A prostaglandin analog according to claim 25, wherein g is
 3. 27. 9-Deoxy-9-methylene-2a,2b-dihomo-15-epi-15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 26. 28. 9-Deoxy-9-methylene-2a,2b-dihomo-15-epi-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 26. 29. A prostaglandin analog according to claim 25, wherein g is
 1. 30. A prostaglandin analog according to claim 29, wherein at least one of R₃ and R₄ is methyl.
 31. 9-Deoxy-9-methylene-15-epi-16-methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 30. 32. A prostaglandin analog according to claim 29, wherein at least one of R₃ and R₄ is fluoro.
 33. 9-Deoxy-9-methylene-15-epi-16,16-difluoro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 32. 34. A prostaglandin analog according to claim 29, wherein R₃ and R₄ are both hydrogen.
 35. 9-Deoxy-9-methylene-15-epi-16-methyl-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 34. 36. A prostaglandin analog according to claim 23, wherein M₁ is ##STR8##
 37. A prostaglandin analog according to claim 36, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 38. A prostaglandin analog according to claim 37, wherein g is
 3. 39. A prostaglandin analog according to claim 38, wherein at least one of R₃ and R₄ is methyl.
 40. 9-Deoxy-9-methylene-2a,3b-dihomo-16-methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-5,6-didehydro-PGF.sub.2, a prostaglandin analog according to claim
 39. 41. A prostaglandin analog according to claim 38, wherein at least one of R₃ and R₄ is fluoro.
 42. 9-Deoxy-9-methylene-2a,3b-dihomo-16,16-difluoro-16-phenyl-17,18,-19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 41. 43. A prostaglandin analog according to claim 38, wherein R₃ and R₄ are both hydrogen.
 44. 9-Deoxy-9-methylene-2a,2b-dihomo-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF.sub.2, a prostaglandin analog according to claim
 43. 45. A prostaglandin analog according to claim 27, wherein g is
 1. 46. A prostaglandin analog according to claim 45, wherein at least one of R₃ and R₄ is methyl.
 47. A prostaglandin analog according to claim 46, wherein R₃ and R₄ are both methyl.
 48. 9-Deoxy-9-methylene-16-methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-5,6-didehydro-PGF₂, tris-(hydroxymethyl)aminomethane salt, a prostaglandin analog according to claim
 47. 49. 9-Deoxy-9-methylene-16-methyl-16-phenyl-18,19,20-trinor-13,14-5,6-didehydro-PGF.sub.2, methyl ester, a prostaglandin analog according to claim
 47. 50. 9-Deoxy-9-methylene-16-methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-5,6-didehydro-PGF₂, methyl ester, a prostaglandin analog according to claim
 47. 51. A prostaglandin analog according to claim 45, wherein at least one of R₃ and R₄ is fluoro.
 52. A prostaglandin analog according to claim 51, wherein R₃ and R₄ are both fluoro.
 53. A prostaglandin analog according to claim 52, wherein R₅ is methyl.
 54. 9-Deoxy-9-methylene-15-methyl-16,16-difluoro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 53. 55. A prostaglandin analog according to claim 52, wherein R₅ is hydrogen.
 56. 9-Deoxy-9-methylene-16,16-difluoro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 55. 57. A prostaglandin analog according to claim 45, wherein R₃ and R₄ are both hydrogen.
 58. A prostaglandin analog according to claim 57, wherein R₅ is methyl.
 59. 9-Deoxy-9-methylene-15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, tris-(hydroxymethyl)aminomethane salt, a prostaglandin analog according to claim
 58. 60. 9-Deoxy-9-methylene-15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, methyl ester, a prostaglandin analog according to claim
 58. 61. 9-Deoxy-9-methylene-15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 58. 62. A prostaglandin analog according to claim 57, wherein R₅ is hydrogen.
 63. 9-Deoxy-9-methylene-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, methyl ester, a prostaglandin analog according to claim
 62. 64. 9-Deoxy-9-methylene-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 62. 65. A prostaglandin analog according to claim 1, wherein Y₂ is trans--CH═CH--.
 66. A prostaglandin analog according to claim 65, wherein Z₉ is --CH₂ --C.tbd.C--(CH₂)_(g) --CH₂ --.
 67. A prostaglandin analog according to claim 66, wherein M₁ is ##STR9##
 68. 9-Deoxy-9-methylene-15-epi-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-PGF₁, a prostaglandin analog according to claim
 67. 69. A prostaglandin analog according to claim 66, wherein M₁ is ##STR10##
 70. A prostaglandin analog according to claim 69, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 71. A prostaglandin analog according to claim 70, wherein g is
 3. 72. 9-Deoxy-9-methylene-2a,2b-dihomo-15-methyl-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-PGF₁, a prostaglandin analog according to claim
 71. 73. 9-Deoxy-9-methylene-2a,2b-dihomo-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-PGF₁, a prostaglandin analog according to claim
 71. 74. A prostaglandin analog according to claim 70, wherein g is
 1. 75. A prostaglandin analog according to claim 74, wherein at least one of R₃ and R₄ is methyl.
 76. A prostaglandin analog according to claim 75, wherein R₃ and R₄ are both methyl.
 77. 9-Deoxy-9-methylene-16-methyl-4,4,5,5-tetradehydro-16-phenyl-18,19,20-trinor-PGF₁, a prostaglandin analog according to claim
 76. 78. A prostaglandin analog according to claim 74, wherein at least one of R₃ and R₄ is fluoro.
 79. A prostaglandin analog according to claim 78, wherein R₃ and R₄ are both fluoro.
 80. 9-Deoxy-9-methylene-16,16-difluoro-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-PGF₁, a prostaglandin analog according to claim
 79. 81. A prostaglandin analog according to claim 74, wherein R₃ and R₄ are both hydrogen.
 82. A prostaglandin analog according to claim 81, wherein R₅ is methyl.
 83. 9-Deoxy-9-methylene-15-methyl-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-PGF₁, a prostaglandin analog according to claim
 82. 84. A prostaglandin analog according to claim 81, wherein R₅ is hydrogen.
 85. 9-Deoxy-9-methylene-4,4,5,5-tetradehydro-16-phenyl-17,18,19,20-tetranor-PGF₁, a prostaglandin analog according to claim
 84. 86. A prostaglandin analog according to claim 65, wherein Z₉ is --CH₂ --C.tbd.C--(CH₂)_(g) --CH₂ --.
 87. A prostaglandin analog according to claim 86, wherein M₁ is ##STR11##
 88. A prostaglandin analog according to claim 87, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 89. A prostaglandin analog according to claim 88, wherein g is
 3. 90. 9-Deoxy-9-methylene-2a,2b-dihomo-15-epi-15-methyl-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 89. 91. 9-Deoxy-9-methylene-2a,2b-dihomo-15-epi-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 89. 92. A prostaglandin analog according to claim 88, wherein g is
 1. 93. A prostaglandin analog according to claim 92, wherein at least one of R₃ and R₄ is methyl.
 94. 9-Deoxy-9-methylene-15-epi-16-methyl-16-phenyl-18,19,20-trinor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 93. 95. A prostaglandin analog according to claim 92, wherein at least one of R₃ and R₄ is fluoro.
 96. 9-Deoxy-9-methylene-15-epi-16,16-difluoro-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 95. 97. A prostaglandin analog according to claim 92, wherein R₃ and R₄ are both hydrogen.
 98. 9-Deoxy-9-methylene-15-epi-15-methyl-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 97. 99. A prostaglandin analog according to claim 86, wherein M₁ is ##STR12##
 100. A prostaglandin analog according to claim 99, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 101. A prostaglandin analog according to claim 100, wherein g is
 3. 102. A prostaglandin analog according to claim 101, wherein at least one of R₃ and R₄ is methyl.
 103. 9-Deoxy-9-methylene-2a,2b-dihomo-16-methyl-16-phenyl-18,19,20-trinor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 102. 104. A prostaglandin analog according to claim 101, wherein at least one of R₃ and R₄ is fluoro.
 105. 9-Deoxy-9-methylene-2a,2b-dihomo-16,16-difluoro-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF.sub.2, a prostaglandin analog according to claim
 102. 106. A prostaglandin analog according to claim 101, wherein R₃ and R₄ are both hydrogen.
 107. 9-Deoxy-9-methylene-2a,2b-dihomo-15-methyl-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 106. 108. A prostaglandin analog according to claim 100, wherein g is
 1. 109. A prostaglandin analog according to claim 108, wherein at least one of R₃ and R₄ is methyl.
 110. A prostaglandin analog according to claim 109, wherein R₃ and R₄ are both methyl.
 111. 9-Deoxy-9-methylene-16-methyl-16-phenyl-18,19,20-trinor-5,6-didehydro-PGF₂, tris(hydroxymethyl)aminomethane salt, a prostaglandin analog according to claim
 110. 112. 9-Deoxy-9-methylene-16-methyl-16-phenyl-18,19,20-trinor-5,6-didehydro-PGF₂, methyl ester, a prostaglandin analog according to claim
 110. 113. 9-Deoxy-9-methylene-16-methyl-16-phenyl-18,19,20-trinor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 110. 114. A prostaglandin analog according to claim 108, wherein at least one of R₃ and R₄ is fluoro.
 115. A prostaglandin analog according to claim 114, wherein R₃ and R₄ are both fluoro.
 116. A prostaglandin analog according to claim 115, wherein R₅ is methyl.
 117. 9-Deoxy-9-methylene-15-methyl-16,16-difluoro-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 116. 118. A prostaglandin analog according to claim 115, wherein R₅ is hydrogen.
 119. 9-Deoxy-9-methylene-16,16-difluoro-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 118. 120. A prostaglandin analog according to claim 118, wherein R₃ and R₄ are both hydrogen.
 121. A prostaglandin analog according to claim 120, wherein R₅ is methyl.
 122. 9-Deoxy-9-methylene-15-methyl-16-phenyl-17,18,19,20-trinor-5,6-didehydro-PGF.sub.2, tris(hydroxymethyl)aminomethane salt, a prostaglandin analog according to claim
 121. 123. 9-Deoxy-9-methylene-15-methyl-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, methyl ester, a prostaglandin analog according to claim
 121. 124. 9-Deoxy-9-methylene-15-methyl-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 121. 125. A prostaglandin analog according to claim 120, wherein R₅ is hydrogen.
 126. 9-Deoxy-9-methylene-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, methyl ester, a prostaglandin analog according to claim
 125. 127. 9-Deoxy-9-methylene-16-phenyl-17,18,19,20-tetranor-5,6-didehydro-PGF₂, a prostaglandin analog according to claim
 125. 